For the past three years, researchers at the Hubrecht Institute in the Netherlands have carefully cataloged and mapped all the proliferating cells in mouse hearts, looking for cardiac stem cells. The elusive cells should theoretically be able to repair the damaged heart muscle, so the stakes to find them were high. Indeed, that research, which has involved many laboratories over decades, has been marked by heated debate and, recently, by an appeal for the retraction of over 30 documents for falsified data. This week, however, Proceedings of the National Academy of Sciences The results of the Hubrecht team's work are announced: no evidence of cardiac stem cells.

This conclusion, which confirms a long suspicion among some in the field, puts at the center of a deeper question – on what it means to be a stem cell. As a more sophisticated technology has revealed how plasm and heterogeneous cell populations may be, some researchers have switched from the visualization of "stem" as the definitive trait of a category of cells to seeing it as a function in which many cell types can perform or contribute.

Stem cells have been identified and characterized for the first time in bone marrow in the 50s and 60s, in an effort to understand and treat the consequences of radiation exposure after World War II. These blood stem cells were rare, slow to divide and capable of both self-renewal and differentiation into any of the more specialized cell types of blood. They kept the tanks of the body of the blood cells and helped him to react to the damage. When they were irradiated, they died and the body had no way to replace them – but bone marrow transplants (which contained stem cells) allowed the system to regenerate.

Because of their relevance to healing and recovery, stem cells from other tissues have become prized rewards among researchers and physicians looking for ways to treat all kinds of conditions and diseases.

Then the story became more complicated. Stem cells have been identified in other adult tissues throughout the body: in the skin, in hair follicles, in the intestine – and a few months ago in the bones. They too could self-renew themselves and give rise to the various cell lines of their tissues. Otherwise, they looked very different from the blood stem cells. They expressed different genes, exhibited different protein and surface markers, and dived in different ways and at different rates.

In the 1990s, scientists isolated embryonic stem cells, which were even more potent than those in adult tissues, with the ability to become any type of cell in the body. Around the same time, scientists have begun to examine the part that cancer stem cells could play in the growth of tumors. And in 2006, researchers managed to transform differentiated connective tissue cells into induced pluripotent stem cells (iPSC), which had the versatility of embryonic stem cells. That result showed that stemness could be induced.

However, relying on these findings, according to the molecular geneticist Hans Clevers, an author on the new cardiac stem cell card, is the assumption that stem cells throughout the body are "a precious, wired magical entity" like those of the bony ones. marrow. In fact, he said, those early insights obtained from blood stem cells have colored the way scientists think of stem cells in other tissues – sometimes in ways that have been profoundly limiting.

Many paths for tissue repair

An often overlooked point is that "many tissues can be repaired in very clever ways," Clevers said. "There is no defined strategy". In the blood, the small population of stem cells is the only means of regeneration, but in solid tissues, it is not always the case. The stem cells themselves are different: they tend to divide more rapidly, for example, and because they have unique molecular profiles, they must be identified by methods specific to them. The dependence on specific tissue markers (which are not always rigorous) is one of the reasons why there has been so much debate about whether or not cardiac stem cells exist – and why it remains so difficult to determine other types of stem cells? .

Furthermore, when the stem cells in the solid tissues are destroyed, the more specialized cells in those tissues can often return to a stem-like state to take on the repair functions on their own. The cells are therefore much more plastic than was thought possible, with less fixed identities. "There is more and more evidence that our bodies can respond to independent damage[ly] of what we would consider a classic stem cell population, "said Jonathan Hoggatt, a hematologist and stem cell researcher at Harvard Medical School and Massachusetts General Hospital.

This has been shown in a number of organs, including the kidneys, lungs, stomach and intestines. Perhaps the most surprising, some tissues (beyond the heart) do not seem to have a stem cell population. The adult liver – the epitome of efficient organ regeneration – has no stem cells; instead, its differentiated cells can act as stem cells when needed. "Essentially," said Clevers, "every liver cell has the potential to behave like a stem cell."

And so "it is more useful to find out how a particular tissue performs its stem function rather than identifying individual stem cells," he said. The way in which the various cells contribute to the maintenance of a tissue constitutes the root – not just any kind of cell or entity. Sticking to the more dogmatic definition of what a "real" stem cell should be, instead of considering that they fall along a more nebulous spectrum, has hampered progress.

In fact, researchers have found that even "real" stem cells vary in power and behavior. "We are learning that there is a lot more heterogeneity in what we thought were rather homogeneous populations," Hoggatt said.

Dubious Stem Cells, Phony Treatments

As it is increasingly difficult to distinguish stem cells from others that have already begun to engage in a differentiated destiny, it may be necessary to revisit the oldest research. Pamela Robey, a biologist of the National Institutes of Health who deals with the skeletal system, thinks that newly identified skeletal stem cells may actually be progenitor cells – the recent, slightly more differentiated stem cell progeny – instead. Current skeletal stem cells, he argues, are even more rare and have yet to be identified. "It's very easy to fool yourself into thinking you have a real stem cell," he said, "when it might not be like that."

This sometimes leads to controversy, particularly when it comes to mesenchymal stem cells, a diversified and multipotent category extracted from the bone marrow, although it does not produce red blood cells. Currently, most researchers do not consider them as stem cells at all (and many have ceased to call them that), but a history of confusion about who they are and what they do has made them "ripe for exploitation," Robey said. . Unapproved stem cell clinics have taken advantage of their controversial status to treat thousands of people with ineffective, unproven, and potentially dangerous therapies. In fact, only a handful of stem cell treatments, using certified stem cells, are permitted by the Food and Drug Administration, and all involve some version of bone marrow or blood cell transplantation.

But for scientists observing the appropriate regulations, a broader definition for stem cells could be good news for medicine: it means regenerative treatments should not target only stem cell populations, which may not always exist. Rather, they could use more differentiated cells that meet some stemlike criteria. Some researchers have decided not to consider staminism as a factor altogether when new drugs involving living cells arise. "It makes life easier," Clevers said.

Going forward, he added, "we have to be more open, more accepting the fact that in principle any cell can be a stem cell".

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